scholarly journals Efficacy of the Investigational Antifungal VT-1161 in Treating Naturally Occurring Coccidioidomycosis in Dogs

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Lisa F. Shubitz ◽  
Michael E. Roy ◽  
Hien T. Trinh ◽  
William J. Hoekstra ◽  
Robert J. Schotzinger ◽  
...  
Keyword(s):  
Low Dose ◽  
Plasma Concentrations ◽  
Clinical Signs ◽  
Weighted Average ◽  
Response To Treatment ◽  
Preclinical Model ◽  
High Dose ◽  
Open Label ◽  
Naturally Occurring ◽  
Reduced Toxicity

ABSTRACT Coccidioidomycosis can be a chronic, systemic fungal infection requiring long-term to lifetime medication. Thus, there is a need for improved antifungal agents with greater efficacy and reduced toxicity. VT-1161 has a low affinity for mammalian cytochromes and potently inhibits fungal CYP51 with proven efficacy in murine models of central nervous system (CNS) and respiratory coccidioidomycosis. Dogs experience coccidioidomycosis similar to humans and are a useful preclinical model for naturally occurring disease. Twenty-four client-owned dogs diagnosed with respiratory coccidioidomycosis based on radiography, serology, clinical signs, and clinicopathologic abnormalities were treated with a loading dose of VT-1161 for 14 days, followed by 46 days of a lower maintenance dose. Twelve dogs received a high dose (29 mg/kg loading, 6 mg/kg maintenance) and 12 received a low dose (10 mg/kg loading, 1.6 mg/kg maintenance). Response to treatment was assessed by calculating the reduction in disease scores at exit compared to disease scores at enrollment. Overall, 20 of 24 (83%) dogs had ≥50% reduction in enrollment disease scores at exit (P < 0.001), with no difference between the high- and low-dose groups (P = 0.66). Time-weighted average plasma concentrations for the high- and low-dose groups were 39 ± 5 μg/ml and 19 ± 2 μg/ml, respectively. In this open-label study, VT-1161 was efficacious for the treatment of respiratory coccidioidomycosis in naturally infected dogs. Combined with previously reported murine data, this finding supports the further development of VT-1161 for the treatment of coccidioidomycosis in humans.

Intensive Initial Oral Anticoagulation and Shorter Heparin Treatment in Deep Vein Thrombosis

1984 ◽  
Vol 52 (03) ◽  
pp. 276-280 ◽  
Author(s):  
Sam Schulman ◽  
Dieter Lockner ◽  
Kurt Bergström ◽  
Margareta Blombäck
Keyword(s):  
Deep Vein Thrombosis ◽  
Oral Anticoagulation ◽  
Dose Group ◽  
Low Dose ◽  
Clinical Signs ◽  
Coagulation Factor ◽  
High Dose ◽  
Vein Thrombosis ◽  
Heparin Treatment ◽  
Deep Vein

SummaryIn order to investigate whether a more intensive initial oral anticoagulation still would be safe and effective, we performed a prospective randomized study in patients with deep vein thrombosis. They received either the conventional regimen of oral anticoagulation (“low-dose”) and heparin or a more intense oral anticoagulation (“high-dose”) with a shorter period of heparin treatment.In the first part of the study 129 patients were randomized. The “low-dose” group reached a stable therapeutic prothrombin complex (PT)-level after 4.3 and the “high-dose” group after 3.3 days. Heparin was discontinued after 6.0 and 5.0 days respectively. There was no difference in significant hemorrhage between the groups, and no clinical signs of progression of the thrombosis.In the second part of the study another 40 patients were randomized, followed with coagulation factor II, VII, IX and X and with repeated venograms. A stable therapeutic PT-level was achieved after 4.4 (“low-dose”) and 3.7 (“high-dose”) days, and heparin was discontinued after 5.4 and 4.4 days respectively. There were no clinical hemorrhages, the activity of the coagulation factors had dropped to the same level in both groups at the time when heparin was discontinued and no thromboembolic complications occurred.Our oral anticoagulation regimen with heparin treatment for an average of 4.4-5 days seems safe and reduces in-patient costs.

Extended-release Buprenorphine, an FDAindexed Analgesic, Attenuates Mechanical Hypersensitivity in Rats (Rattus norvegicus)

2021 ◽  
Author(s):  
Eden D Alamaw ◽  
Benjamin D Franco ◽  
Katechan Jampachaisri ◽  
Monika K Huss ◽  
Cholawat Pacharinsak
Keyword(s):  
Extended Release ◽  
Low Dose ◽  
Clinical Signs ◽  
High Dose ◽  
Male Adult ◽  
Pain Model ◽  
Mechanical Hypersensitivity ◽  
Treatment Groups ◽  
Incisional Pain ◽  
Thermal Hypersensitivity

A new extended-release buprenorphine (XR), an FDA-indexed analgesic, has recently become available to the laboratoryanimal community. However, the effectiveness and dosing of XR has not been extensively evaluated for rats. We investigatedXR’s effectiveness in attenuating postoperative hypersensitivity in a rat incisional pain model. We hypothesized that highdose of XR would attenuate mechanical and thermal hypersensitivity more effectively than the low dose of XR in this model. We performed 2 experiments. In experiment 1, male adult Sprague–Dawley rats (n = 31) were randomly assigned to 1 of the 4 treatment groups: 1) saline (saline, 0.9% NaCl, 5 mL/kg, SC, once); 2) sustained-release buprenorphine (Bup-SR; 1.2 mg/kg, SC, once), 3) low-dose extended-release buprenorphine (XR-Lo; 0.65 mg/kg, SC, once), and 4) high-dose extended-releasebuprenorphine (XR-Hi; 1.3 mg/kg, SC, once). After drug administration, a 1 cm skin incision was made on the plantar hind paw under anesthesia. Mechanical and thermal hypersensitivity were evaluated 1 d before surgery (D-1), 4 h after surgery (D0), and for 3 d after surgery (D1, D2, and D3). In experiment 2, plasma buprenorphine concentration (n = 39) was measured at D0, D1, D2, and D3. Clinical observations were recorded daily, and a gross necropsy was performed on D3. Mechanical and thermal hypersensitivity were measured for 3 d (D0-D3) in the saline group. Bup-SR, XR-Lo, and XR-Hi effectively attenuated mechanical hypersensitivity for D0-D3. Plasma buprenorphine concentrations remained above 1 ng/mL on D0 and D1 in all treatment groups. No abnormal clinical signs were noted, but injection site reactions were evident in the Bup-SR (71%), XR-Lo (75%), and XR-Hi (87%) groups. This study indicates that XR-Hi did not attenuate hypersensitivity more effectivelythan did XR-Lo in this model. XR 0.65 mg/kg is recommended to attenuate postoperative mechanical hypersensitivity for upto 72 h in rats in an incisional pain model.

P061 Kawasaki disease: a case series from a tertiary Hospital in Kenya

Rheumatology ◽  
2021 ◽  
Vol 60 (Supplement_5) ◽  
Author(s):  
C Njeru ◽  
A Migowa
Keyword(s):  
Kawasaki Disease ◽  
Incidence Rate ◽  
Low Dose ◽  
Clinical Signs ◽  
Case Series ◽  
Cervical Lymphadenopathy ◽  
Patient Characteristics ◽  
Tertiary Hospital ◽  
High Dose ◽  
True Incidence

Abstract Background Kawasaki disease (kDa) is a childhood vasculitides that affects small and medium-sized arteries. It is self-limiting but when left untreated can cause coronary artery aneurysms in about 25% of children1. The diagnosis is clinical and is made with the criteria of fever for at least five days, and at least four out of five other clinical signs: bilateral non-exudative conjunctivitis, oral mucous membrane changes, peripheral extremity changes, polymorphous rash, and cervical lymphadenopathy. Incomplete kDa is diagnosed with fever for at least five days and at least 2–3 of the principal signs, with suggestive lab investigations and lack of an alternative diagnosis1. kDa is named after Dr Tomisaku Kawasaki who first described it in 1967 in Japan2. The highest incidence of kDa continues to be reported among Asian children, with an incidence rate of 264.8 per 100 000 population aged 0–4 years as per Japan’s latest nationwide survey3. In Africa, the true incidence is unknown but several case reports have been published. A 2016 paper by Gorrab et al.4 found that the annualized incidence rate of kDa in the Maghreb children living in Quebec (18.49/year/100 000 children under 5 years of age) was 4–12 times higher than reported in their countries of origin- Tunisia, Morocco, and Algeria (0.95, 4.52, and 3.15, respectively) suggesting a likelihood of under-diagnosis. This case series sought to highlight the characteristics, presentation, and management of patients diagnosed with kDa in a tertiary hospital in Kenya. Methods This was a retrospective cross-sectional study carried out by reviewing the charts of all the patients with a discharge diagnosis of kDa from January 2013 to December 2017 at the Aga Khan University Hospital, Nairobi. Their demographics, presentation, diagnostic work-up, and management are reported. Analysis was done by descriptive statistics using the Microsoft Excel 2016 Application. Results A total of 15 cases were identified and the patient characteristics and presentation are as tabulated below: In addition to elevated inflammatory markers (C reactive protein and/or Erythrocyte Sedimentation Rate), a significant number of the patients also had sterile pyuria (9/9), hypoalbuminemia (8/10), thrombocytosis (8/15), and anaemia (11/15). Nine out of eleven had negative blood cultures. Fourteen out of the fifteen patients had echocardiograms done during admission. Only one patient was found to have abnormal findings of bilaterally dilated coronaries arteries. Five patients had at least one documented repeat echocardiogram. Fourteen patients received Intravenous Immunoglobulin (IVIG), with 13 of them responding to treatment. No adverse effects were reported after treatment. One patient did not improve and needed a second dose of IVIG and intravenous methylprednisone (30 mg/kg). Fourteen patients received aspirin but dosing varied from high (80–90 mg/kg/day) to moderate (30–50 mg/kg/day) to low dose (3 mg/kg/day). One patient on high-dose aspirin was noted to have developed symptoms consistent with aspirin-induced bronchospasm and was changed to low dose. Conclusion This case series highlights the presence of kDa in the Kenyan pediatric population with patient characteristics similar to what is reported globally. Diagnosis was made after a mean of about 7 days, possibly due to low awareness of the disease among healthcare professionals. Management with IVIG in most cases was successful but more guidance is needed around the use of steroids and the dosing of aspirin.

scholarly journals Conception Rate and Reproductive Hormone Secretion in Holstein Cows Immunized against Inhibin and Subjected to the Ovsynch Protocol

Animals ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 313 ◽  
Author(s):  
Rihong Guo ◽  
Fang Chen ◽  
Cheng Mei ◽  
Zicun Dai ◽  
Leyan Yan ◽  
...  
Keyword(s):  
Dairy Cows ◽  
Reproductive Performance ◽  
Luteal Phase ◽  
Low Dose ◽  
Follicle Stimulating Hormone ◽  
Hormone Secretion ◽  
Plasma Concentrations ◽  
High Dose ◽  
Reproductive Hormone ◽  
Conception Rates

This study was conducted to investigate the feasibility of improving fertility in dairy cows via immunization against inhibin. Thirty-two cows were divided into Control (n = 11), Low-dose (n = 10) and High-dose (n = 11) groups. The High-dose and Low-dose cows were treated with 1 and 0.5 mg of the inhibin immunogen, respectively. All the cows were subjected to the Ovsynch protocol from the day of antigen administration and were artificially inseminated. Blood samples were serially collected over a 24-day period from the start of the Ovsynch protocol to 14 days after insemination. The results showed that immunization against inhibin dose-dependently increased the plasma concentrations of follicle-stimulating hormone (FSH), estradiol (E2), and activin A, but decreased progesterone (P4) concentrations in the luteal phase. Immunization also increased the plasma interferon (IFN)-τ concentrations in pregnant cows on day 14 after initial insemination. The conception rates in High-dose (45.5%) and Low-dose (40%) cows marginally increased compared to that in Control cows (27.3%), but the increases were not significant (p > 0.05). In conclusion, a single immunization against inhibin has the potential to improve conception rates, despite impaired luteal development. To further improve the reproductive performance of dairy cows, additional luteal-stimulating treatments are suggested in combination with immunization against inhibin and Ovsynch techniques.

Effects of acetylsalicylic acid on pulmonary vascular tone and membrane permeability in blood-perfused dog lung

1993 ◽  
Vol 75 (6) ◽  
pp. 2561-2569 ◽  
Author(s):  
K. Kambara ◽  
M. Arakawa ◽  
T. Segawa ◽  
F. Ando ◽  
M. Ohno ◽  
...  
Keyword(s):  
Acetylsalicylic Acid ◽  
Extravascular Lung Water ◽  
Vascular Tone ◽  
Low Dose ◽  
Pressor Response ◽  
Plasma Concentrations ◽  
High Dose ◽  
Constant Flow ◽  
Lung Water ◽  
Pulmonary Vasoconstriction

We studied the effects of acetylsalicylic acid (ASA) on pressor response, microvascular filtration coefficient (Kf), extravascular lung water, and plasma concentrations of cyclooxygenase- and 5-lipoxygenase-derived products in 21 blood-perfused dog lungs with constant flow. The lungs were perfused for 1 h with an intrapulmonary injection of saline as vehicle (n = 5), a low dose of ASA [136 +/- 25 (SD) micrograms/ml perfusate; n = 5], a high dose of ASA (1,006 +/- 278 micrograms/ml perfusate; n = 6), or alloxan (1,000 mg; n = 5). Alloxan significantly increased Kf and extravascular lung water, whereas neither the low nor high dose of ASA increased Kf or extravascular lung water. The ASA-induced increase in vascular resistance did not correlate with the extent of the decrease in perfusate 6-keto-prostaglandin F1 alpha or the ratio of perfusate 6-ketoprostaglandin F1 alpha to thromboxane B2. Moreover, ASA did not enhance the generation of perfusate leukotrienes B4, D4, or E4. We conclude that pulmonary microvascular permeability is unaltered by ASA and that neither the decrease in plasma prostacyclin nor the increase in plasma sulfidopeptide leukotrienes may account for ASA-induced pulmonary vasoconstriction.

Pathology of Angiostrongylus cantonensis infection in two model avian hosts

Parasitology ◽  
2020 ◽  
pp. 1-4
Author(s):  
Barbora Fecková ◽  
Priyanka Djoehana ◽  
Barbora Putnová ◽  
Michaela Valašťanová ◽  
Michaela Petríková ◽  
...  
Keyword(s):  
Low Dose ◽  
Natural Infection ◽  
Clinical Signs ◽  
French Polynesia ◽  
Angiostrongylus Cantonensis ◽  
High Dose ◽  
Wide Range ◽  
The Central Nervous System ◽  
Gross Lesions ◽  
Natural Pest Control

Abstract Angiostrongylus cantonensis causes severe neurological disorders in a wide range of warm-blooded animals, including several avian species. A laboratory isolate of A. cantonensis originating from French Polynesia, genotyped as clade 2, was used to assess the effect of experimental infection in chicken and Japanese quail. Low dose groups of birds were infected orally by 100 L3 larvae, high dose groups by 1500 L3 larvae and the birds in the third group were fed three infected snails, mimicking a natural infection. Clinical signs during the first week after infection, haematology, biochemistry, gross lesions and histology findings were used to assess the pathology of the infection. Some of the infected birds showed peripheral eosinophilia, while mild neurological signs were seen in others. No larvae were observed in serial sections of the central nervous system of infected birds 1 week after infection and no major gross lesions were observed during necropsy; histopathology did not reveal lesions directly attributable to A. cantonensis infection. Our results suggest that galliform birds are not highly susceptible to A. cantonensis infection and open a question of the importance of Galliformes in endemic areas as natural pest control, lowering the number of hosts carrying the infective larvae.

Effect of human recombinant superoxide dismutase on canine myocardial infarction

1990 ◽  
Vol 258 (2) ◽  
pp. H369-H380 ◽  
Author(s):  
B. S. Patel ◽  
M. O. Jeroudi ◽  
P. G. O'Neill ◽  
R. Roberts ◽  
R. Bolli
Keyword(s):  
Superoxide Dismutase ◽  
Infarct Size ◽  
Low Dose ◽  
Coronary Occlusion ◽  
Plasma Concentrations ◽  
Control Group ◽  
High Dose ◽  
Collateral Flow ◽  
Tetrazolium Chloride ◽  
Arterial Blood

To determine whether human recombinant superoxide dismutase (h-SOD) produces sustained reduction of infarct size, anesthetized dogs underwent a 2-h coronary occlusion followed by either 48 or 4 h of reperfusion. In the 48-h study, dogs were randomized to three intravenous treatments: 1) “low-dose” h-SOD (2 mg/kg bolus 2 min before reperfusion followed by 4 mg/kg over 45 min), 2) “high-dose” h-SOD (8 mg/kg bolus 2 min before reperfusion followed by 8 mg/kg over 45 min), or 3) equivalent volumes of saline. In the 4-h study, dogs were randomized to high-dose h-SOD or saline. Occluded bed size was measured by postmortem perfusion and infarct size by triphenyl tetrazolium chloride staining and planimetry. Investigators performing the study and measuring infarct size were blinded to the treatment given. High plasma concentrations of h-SOD were present in the arterial blood of treated dogs in the early phase of reperfusion (greater than 60 and greater than 180 micrograms/ml in low- and high-dose groups, respectively). In both studies, control and treated groups were similar with respect to occluded bed size, collateral blood flow, and rate-pressure product during ischemia. In the 48-h study, infarct size, expressed as percent of occluded bed size, was 41.3 +/- 7.6% (mean +/- SE) in the control group, 37.1 +/- 7.2% in the low-dose h-SOD group, and 48.0 +/- 7.1% in the high-dose h-SOD group. In the 4-h study, infarct size was 30.6 +/- 4.9% in the control group and 31.5 +/- 9.6% in the high-dose h-SOD group. Analysis of the flow-infarct relationships confirmed that h-SOD did not reduce infarct size at any level of collateral flow in either the 48- or 4-h study. Recovery of regional myocardial function after reperfusion was also unaffected by h-SOD in both studies. Thus in this randomized blinded study, large doses of h-SOD given at the time of reperfusion failed to limit infarct size or enhance recovery of function, both early (4 h) and late (48 h) after reperfusion following a 2-h coronary occlusion.

scholarly journals Chronic Subclinical Prion Disease Induced by Low-Dose Inoculum

2002 ◽  
Vol 76 (5) ◽  
pp. 2510-2517 ◽  
Author(s):  
Alana M. Thackray ◽  
Michael A. Klein ◽  
Adriano Aguzzi ◽  
Raymond Bujdoso
Keyword(s):  
Brain Tissue ◽  
Prion Disease ◽  
Low Dose ◽  
Clinical Signs ◽  
Rocky Mountain ◽  
Rapid Onset ◽  
Distinct Pattern ◽  
High Dose ◽  
Terminal Disease ◽  
Subclinical Disease

ABSTRACT We have compared the transmission characteristics of the two mouse-adapted scrapie isolates, ME7 and Rocky Mountain Laboratory (RML), in tga20 mice. These mice express elevated levels of PrP protein compared to wild-type mice and display a relatively short disease incubation period following intracerebral prion inoculation. Terminal prion disease in tga20 mice induced by ME7 or RML was characterized by a distinct pattern of clinical signs and different incubation times. High-dose RML inoculated intracerebrally into tga20 mice induced the most rapid onset of clinical signs, with mice succumbing to terminal disease after only 58 ± 3 days. In contrast, high-dose ME7 gave a mean time to terminal disease of 74 ± 0 days. Histological examination of brain sections from prion-inoculated tga20 mice at terminal disease showed that ME7 gave rise to a more general and extensive pattern of vacuolation than RML. Low-dose inoculum failed to induce terminal disease but did cause preclinical symptoms, including the appearance of reversible clinical signs. Some mice oscillated between showing no clinical signs and early clinical signs for many months but never progressed to terminal disease. Brain tissue from these mice with chronic subclinical prion disease, sacrificed at >200 days postinoculation, contained high levels of infectivity and showed the presence of PrPSc. Parallel analysis of brain tissue from mice with terminal disease showed similar levels of infectivity and detectable PrPSc. These results show that high levels of infectivity and the presence of the abnormal isomer of PrP can be detected in mice with subclinical disease following low-dose prion inoculation.

Pooling of Laying Hen Environmental Swabs and Efficacy of Salmonella Detection

2020 ◽  
Vol 83 (6) ◽  
pp. 943-950
Author(s):  
DEANA R. JONES ◽  
RICHARD K. GAST ◽  
PRAFULLA REGMI ◽  
GARRETT E. WARD ◽  
KENNETH E. ANDERSON ◽  
...  
Keyword(s):  
Salmonella Typhimurium ◽  
Salmonella Enteritidis ◽  
Low Dose ◽  
High Dose ◽  
Environmental Testing ◽  
Naturally Occurring ◽  
Rate Of Recovery ◽  
High Doses ◽  
The U.S ◽  
Salmonella Heidelberg

ABSTRACT Environmental testing for Salmonella Enteritidis is required for U.S. shell egg producers with ≥3,000 hens on a farm. The egg producer assumes all costs for the mandatory testing. According to the U.S. Food and Drug Administration (FDA) Egg Rule, either manure scraper or drag swabs can be collected according to published guidelines and requirements. The present study was undertaken to determine the efficacy of Salmonella detection with one-, two-, and four-swab pools of either manure scraper or drag swabs. Resistant isolates of Salmonella serovars Enteritidis (1,000 ppm of streptomycin), Heidelberg (200 ppm of nalidixic acid [NA]), Typhimurium (200 ppm of NA), and Kentucky (200 ppm of NA) were utilized. Low (approximately 8.4 CFU) and high (approximately 84 CFU) levels of inocula were introduced onto a single swab within a pool. Single flocks from each conventional cage (manure scraper swabs) and cage-free barn (drag swabs) were monitored throughout the study at the ages required under the FDA Egg Rule. The highest and most consistent recovery of inoculum was found in single swab samples. For low dose inocula, recovery of isolates was low from single manure scraper swabs (57.9 to 29.2%) and decreased as more swabs were added to the pool. Recovery of isolates from manure scraper swabs was higher for high dose inocula, although Salmonella Heidelberg was outcompeted by the naturally occurring flora and had the lowest rate of recovery among the isolates tested. One- and two-swab pools of drag swabs had similar rates of recovery at both low and high doses for Salmonella Enteritidis, Salmonella Heidelberg, and Salmonella Typhimurium. When Salmonella Enteritidis and Salmonella Kentucky were combined in an inoculum, Salmonella Enteritidis was recovered at a much higher rate than was Salmonella Kentucky for all types of swabs and doses of inocula. Pooling of two drag swabs allowed for similar detection of low and high dose Salmonella, but the pooling of manure scraper swabs decreased detection of low dose Salmonella. HIGHLIGHTS

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